Severe immune response kills SARS victims

An excessive immune reaction appears to be the fatal factor in patients who die of SARS, according to medical data from Hong Kong. The best estimate of the fatality rate of SARS is rising steadily and so understanding how the disease causes death is critical to finding the best treatments.

Scientists have also discovered that the SARS virus can remain viable for at least 24 hours after being deposited in a droplet on a plastic surface - a simulation, for example, of an infected person coughing on to the wall of a lift.

The new information was revealed by Klaus Stöhr, the World Health Organization's chief scientist for SARS in a briefing earlier this week. "In the first week or so of disease the virus is replicating mainly in the upper respiratory tract, causing high fever and dry cough. But in the second week we see an over-reaction of the immune response, and in 20 per cent of cases that leads to very severe disease."

Mark Salter, WHO's coordinator for the clinical management of SARS, told New Scientist that this excessive response seems to be destroying the alveoli, the tiny sacs at the end of the lung tubing where the oxygen is absorbed. It is like stripping all the leaves from a tree, he says, making breathing extremely difficult.

"The immune response develops, but then continues growing unchecked" says Salter. "You then get cytokines, tumour necrosis factor and so on released not just at the virally infected cells they are supposed to kill, but throughout the tissue". This also happens in other diseases but the mechanism is not entirely understood, and certainly not in the case of SARS, he says.

Nevertheless the observation significantly strengthens the basis on which doctors can select the treatments given to patients. In particular, it suggests the use of corticosteroids, alongside other drugs that reduce the viral load such as interferon.

Corticosteroids suppress the immune system and are normally used against asthma, rheumatoid arthritis and in transplant patients to reduce the risk of rejection.

Their use does raise the risk of further infection, but Hong Kong hospitals are claiming success with combinations of the antiviral ribavirin and pulsed steroids, says Salter: "And once steroids are stopped, they see a flare up of the condition suggesting there is a significant immune component to the disease."

. The issue of how long the virus survives outside the body was also raised by Stöhr. Some scientists have argued that long survival could explain unusual cases of transmission in Hong Kong and Canada.

In a study in Germany reported by Stöhr, the virus was dropped in liquid on to a plastic surface, the drop was dried, and examined after 24 hours. "There were 10,000 virus units per millitre before, and after 24 hours there were 1000 - and that was viable viruses."

Prospective study of the clinical progression and viral load of SARS associated coronavirus pneumonia in a community outbreak

JSM Peiris, CM Chu, VCC Cheng, KS Chan, IFN Hung, LLM Poon, KI Law, BSF Tang, TYW Hon, CS Chan, KH Chan, JSC Ng, BJ Zheng, WL Ng, RWM Lai, Y Guan, KY Yuen and members of the HKU / UCH SARS Study Group

This paper has been accepted by The Lancet and will be published next week. We are grateful to The Lancet for the permission to publish the summary of this paper in advance.

Summary

Background:

A community outbreak of severe acute respiratory distress syndrome (SARS) with epidemiological linkage was reported. The temporal progression of the clinical, radiological, and virological changes was investigated.

Methods:

A prospective study of the clinical, haematological, radiological, and microbiological findings of 75 patients managed with a standardized treatment protocol of the Hospital Authority, Hong Kong Special Administrative Region using ribavirin and corticosteroid was performed over a 3 week period. The pattern of clinical disease, viral load, the risk factors for a poor clinical outcome and the usefulness of virological diagnostic methods was presented and analyzed.

Findings:

The fever and pneumonia initially responded to treatment. However, patients developed recurrent fever (85.3%) on day 8.9 ± 3.1 (range 4 to 18), watery diarrhoea (73.3%) on day 7.5 ± 2.3 (range 3 to 15), radiological deterioration (80%) on day 7.4 ± 2.2 (range 3 to 13) and respiratory deterioration (45.3%) on day 8.6 ± 3 days (range 5 to 19). In 45.3% of patients, marked improvement of initial pulmonary lesions was closely associated with appearance of new radiological lesions at other sites. Twenty percent progressed to acute respiratory distress syndrome (ARDS) during the third week. Quantitative RT-PCR of nasopharyngeal aspirates in 14 patients (4 had ARDS and 10 without ARDS) consistently demonstrated a peak viral load at day 10 and a decrease to admission level at day 15. Age and chronic HBV infection are independent significant risk factors for progression to ARDS on multivariate analysis. Faecal excretion of coronavirus was present and continued through the period of follow-up. Seroconversion and RT-PCR of nasopharyngeal aspirates and stool are useful for confirmation of SARS.

Interpretation:

The consistent clinical progression, shifting radiological infiltrates and an inverted V viral load profile suggested that deterioration during the second week is not related to uncontrolled viral replication but may rather be related to immunopathological damage. Age and HBV status are risk factors for progression to ARDS.

http://www.who.int/csr/sars/prospectivestudy/en/index.html

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